Anticancer activity promoted by ligand diversity in diiron thiocarbyne complexes

Mononuclear iron (II) complexes have been intensively investigated with the aim of developing efficacious anticancer drugs that can overcome the serious limitations associated with the platinum complexes currently employed in chemotherapy. Combining a promising antitumor potential with appropriate physicochemical properties, such as aqueous stability and a balanced hydrophilic/lipophilic character, is essential for clinical progression. We prepared six highly functionalized diiron(I) complexes from the μ-thiocarbyne precursor [Fe₂Cp₂(CO)₂(μ-CO)(μ-CSMe)]CF₃SO₃, 1 (Cp = η⁵-C₅H₅), through the substitution of one carbonyl ligand with isocyanides (2-4) and the subsequent substitution of a second CO with N- or P-ligands (5-7). All products 2-7 were structurally characterized using IR and multinuclear NMR spectroscopy. One compound from series (7) was also characterized by single crystal X-ray diffraction. Complexes 2-7 exhibit outstanding stability in physiological-like solutions, with 92-97 % of the compounds unchanged after storing in DMEM at 37 °C for 24 h, and substantial amphiphilicity, with most of Log P_ow values falling in the range -1 to +1. Complexes 3, 4, 5 and 7 exhibited cytotoxic activity against human (HCT 116, MCF-7, A2780) and murine (CT26, 4T1, B16-F1, B16-F10) cancer cell lines with IC₅₀ values up to the nanomolar range, along with moderate selectivity toward the malignant phenotype. The induction of cell differentiation, senescence, and apoptotic cell death with cell-specific redox response were in the background of cytotoxic activity. However, limited tumor volume reduction and observed systemic toxicity in vivo indicated the need for additional structure-activity relationship studies to optimize the compounds anticancer profile.